The Flavivirus genus contains many viruses of considerable medical importance including the dengue virus, the yellow fever virus and the West Nile virus. Resistance to flavivirus infection has been reported in a few laboratory strains of mice and the genetic basis of the resistance has been determined recently. Susceptible mice differ from resistant mice by a nonsense mutation in exon 4 of the Oaslb gene. The main goal of this project is to investigate the evolution of flavivirus resistance in mice by determining the nature and the strength of the evolutionary forces that have influenced the evolution of the Oaslb gene. This study should significantly increase our understanding of the host-species response to flavivirus infection as well as the molecular and cellular mechanisms responsible for flavivirus pathogenicity. Our first aim is to assess the polymorphism of the resistance gene (Oaslb) in wild-derived strains of house mice and in natural populations. The rationale behind searching for additional alleles is that traditionally used laboratory strains represent a poor sample of the flavivirus-resistance alleles that occur in nature. In our second aim we will characterize the phenotypic differences between Oaslb alleles by challenging wild-derived mouse strains with the Modoc virus. One of the reasons for using the Modoc virus is that it induces encephalitis in rodents [unreadable] with symptoms and long term effects similar to those observed in humans infected by the West Nile virus and Japanese encephalitis virus. The viral infection and propagation will be examined at the individual level and at the tissue and cellular level. In our third aim we will analyze the molecular evolution of flavivirus-resistance. The goal is to determine the origin of flavivirus resistance and the origin of the allelic polymorphism at the Oaslb locus. The Oaslb gene will be sequenced in other murine rodents to determine the phylogenetic context of the evolution of flavivirus-resistance. Oas1 b sequences will be analyzed using phylogenetic methods and statistical methods that detect natural selection at the molecular level. [unreadable] [unreadable] [unreadable]